Interpretive Summary: Chickens succumbing to Marek’s disease (MD) exhibit the clinical signs of paralysis and blindness, which can be attributed to nerve enlargements and lymphomas. This serious problem for the poultry industry is caused by the Marek’s disease virus (MDV), a highly infectious and pathogenic herpesvirus. While vaccines can prevent tumor formation, they are not sterilizing, thus, MDV can continue to replicate and spread to other birds. In this paper, we address the molecular question of how MDV causes cancers in chickens. Our results indicate that MDV integrates into the chicken genome near telomere repeats, which are the ends of chromosomes and function to protect chromosomes during cell division. Furthermore, most of the tumors are clonal, which suggests that there is an initial tumor followed by metastasis to other organs. This information is of particular interest to scientists working on herpesvirus replication and spread, and is relevant to the development of new MD vaccines.

Technical Abstract:
Marek’s disease (MD) is a highly contagious neoplastic disease resulting from a cell-associated oncogenic herpesvirus, Marek’s disease virus (MDV) that induces lymphoid tumors in chickens, its natural host. Genomic interactions between virus and host, and their involvement in the process of tumorigenesis and pathogenesis remain unclear. Several herpesviruses, MDV included, have been shown to exist in an integrated state during latent periods of infection, perhaps facilitating host-virus genome interactions. To investigate the features of the integration of MDV DNA into the chicken host genome, late-stage MDV-induced lymphomas were profiled and mapped for integration sites. We found the MDV genome to be exclusively integrated into the telomeric array repeat regions of the host chromosomes. Identification of the chromosomes involved in viral integration events allowed for clonal analysis of lymphomas both within individuals and across multiple individuals. Analysis indicates mostly clonal relationships among tumors within birds as a feature of the diseased state. However, this is not completely exclusive in that apparently non-clonal tumors (as per integration profiles) were also observed. Characterization of MDV integrations provides data to elucidate the latency and cellular transformation mechanisms of a lymphotrophic herpesvirus.